Alzheimer Research Award

Find out more about the winners of our Alzheimer's Research Award and their research projects.

Research Award 2021 – Prof. Dr. Dorothee Dormann

Dorothee Dormann, Professor of Molecular Cell Biology at JGU Mainz.

A well-known pathological feature of Alzheimer's disease are neurofibrillary tangles that contain the protein Tau. Tau aggregates first form in only a few nerve cells, from where they spread to other brain regions. We assume that the process of Tau oligomerization ultimately leads to neuronal dysfunction and the typical symptoms of Alzheimer's disease. Another protein that is deposited in the brain in up to 50% of Alzheimer's patients and is thus impaired in its function is the TDP-43 protein. This protein is known to play an important pathological role in other neurodegenerative diseases, such as frontotemporal dementia and amyotrophic lateral sclerosis. Alzheimer's patients with Tau and TDP-43 aggregates show a more severe brain shrinkage and cognitive decline than patients that have only Tau deposits, suggesting an important contribution of TDP-43 to neurodegeneration in Alzheimer's disease.

How TDP-43 deposits arise in Alzheimer's disease and whether TDP-43 and Tau influence each other’s pathology is currently unknown. With financial support from the Alzheimer Research Prize 2021, we would like to investigate using test tube (in vitro) and cell experiments whether Tau and TDP-43 mutually influence their aggregation and spreading from cell to cell. We would also like to investigate which of the two pathologies occurs first in Alzheimer's patients, and how TDP-43 aggregates are taken up by nerve cells. This research will help us to better understand the molecular basis of TDP-43 and Tau dysfunction in Alzheimer's disease and to gain new mechanistic insights into Alzheimer's and related dementias. An understanding of the molecular disease mechanisms is an important prerequisite for the development of new approaches for the prevention, diagnosis and treatment of these currently incurable dementias.

CV

Dorothee Dormann was born in Schorndorf (Germany) and studied biochemistry at Eberhard Karls University in Tübingen. She completed her graduate studies at Rockefeller University in New York, where she received a Ph.D. in the field of cell biology / immunology in 2007. From 2007 to 2013, as a postdoc in Christian Haass' laboratory (Adolf Butenandt Institute, LMU Munich), she investigated the molecular causes of TDP-43 and FUS dysfunction in amyotrophic lateral sclerosis and frontotemporal dementia. From 2014 to 2021 she headed an independent Emmy Noether junior research group at the Biomedical Center of LMU Munich. Since April 2021 Dorothee Dormann is a Heisenberg Professor for Molecular Cell Biology at Johannes Gutenberg University Mainz and Adjunct Director at the Institute for Molecular Biology (IMB). Her research focuses on the molecular mechanisms of protein mislocalization and aggregation in neurodegenerative diseases. For her research, she was already awarded the Heinz Maier-Leibnitz Prize of the German Research Foundation (2014) and the Paul Ehrlich and Ludwig Darmstädter Award for Young Researchers (2019). Dorothee Dormann is married and has two children.

Research Award 2020 – Dr. Henne Holstege

Henne Holstege, Assistant Professor at the Amsterdam UMC.

Why do some individuals suffer from symptoms of dementia at 70, while other reach ages over 100 years without any signs of cognitive decline? One extreme example is Mrs. van Andel-Schipper: she reached 115 years without a trace of dementia. Her mother also turned 100, and her brain was also raiser-sharp up until the day of her death. Indeed, previous research had shown that reaching extreme old age with maintained cognitive health runs in families. I found that so fascinating that I set out to investigate the genetics factors that play a role in escaping dementia. Mrs. van Andel was only one person, and to find out how it is possible to live to an extreme age without dementia, it is necessary to investigate more individuals just like her, extremely old and cognitively healthy. Therefore, I set up the 100-plus Study cohort of cognitively healthy centenarians in 2013, and we have now collected data from more than 400 healthy centenarians.

First, we need to determine how well the brain of the over 100 functions. To do so, we visit the centenarians and we test their brain-function using neuropsychological tests. We test whether the centenarians can still plan, reason or calculate, and whether memory functions still work properly. We also examine the participants' blood, and about a third of people over 100 are willing to donate their brains after they die. From the blood we isolate DNA, and also the cells of the immune system. More and more studies show that the immune system plays a role in the development of dementia. Indeed, our findings indicate that the genetic risk factors associated with the escape of dementia are often involved in the functioning of the immune system. Part of our studies involve the use genetic material and the blood cells from the centenarians to better understand how their immune systems differ from people who do develop dementia.

Our genes determine whether we become tall or short, whether someone has blond hair or black hair, brown eyes or green eyes. But the vulnerability for developing Alzheimer’s disease is also for ~60-80% defined by our genes. We can use this to our advantage: we can use genetics to predict who will eventually develop dementia before the disease manifests itself. This enables the application of personalized treatment before the disease has inflicted any damage to the brain. In addition, if we can figure out how the genes of the centenarians are involved in maintaining their brain-health, we may be able to mimic the function of those genes in by designing a drug for dementia that achieves the same. This way, we can learn from the centenarians how to maintain human brain-health.

In the centenarian-genomes we look at the genetic "abnormalities" that prevent someone from developing dementia. In our study, we investigate the extremes. In contrast, several hereditary abnormalities are known to cause or increase the risk of dementia. For example, some genetic disorders cause a build-up of amyloid-beta protein in the brain, and carriers of such a genetic disorder are almost certain to develop Alzheimer's disease. Identifying these risk-increasing genes is also part of our study. We are now leading an international effort that explores >50,000 genomes from individuals with or without Alzheimer’s Disease, and we recently found that certain abnormalities within new genes can also be involved in the development of dementia.

While my own expertise lies directly on the genetic backgrounds of cognitive decline and escape thereof, much of the research we perform depends on long-term standing collaborations with other researchers with other expertise, both inside and outside the Amsterdam UMC, and also with researchers abroad. I am well aware that only with these collaborative efforts we can gain maximum revenue from the data and biomaterials we collect in context of the 100-plus Study. It is a true privilege to work with so many inspired people with different expertise. Such collaborations, especially those involving human material, can only be possible if we ensure to follow international research-agreements Therefore, to continue these national and international collaborations, I aim to use the support of the Alzheimer Research Award 2020 issued by the Hans und Ilse Breuer Foundation.

My hope is that our studies of the genetics of the healthy centenarians, their immune systems and their brains can teach us how a human brain can stay healthy until a very old age and to contribute to a future in which far fewer people will suffer from terrible symptoms inflicted by dementia.

CV

Henne Holstege was born on November 14th, 1975 in Rotterdam (The Netherlands).
She studied chemistry at Leiden University in The Netherlands and obtained her degree in 2001. In 2002, she started her PhD in the group of Jos Jonkers at the Netherlands Cancer Institute. Since 2010 she works at the Amsterdam University Medical Center, at the Department of Clinical Genetics and the Alzheimer Center. In 2013, she started the 100-plus Study and since 2015 she is Assistant Professor at the Amsterdam UMC. Currently, she heads a new section at the Department of Clinical Genetics, where her group investigates the genomics of aging, with a strong focus on neurodegenerative diseases. Henne Holstege is married and has three daughters.

Research Award 2020 – Dr. Jochen René Thyrian

According to current figures, around 1.7 million people in Germany suffer from dementia. This disease is one of the most common diseases, and the trend is rising. Mainly older people are affected by this and the situations in which they live are very different. This is based on various life paths, experiences, concomitant diseases, regional and other factors.

The health system is basically very well positioned to ensure good care for people with dementia. There are very good diagnostic methods, also in international comparison, a well-developed network of resident doctors, specialized facilities, various care offers, etc. There are guidelines for care, a wide range of advice from various providers is available. Nevertheless, there are great differences in the supply and it is not yet possible to speak of a systematic, nationwide available and used, high-quality supply for everyone. This finding is based on my own research to date, but there is also consensus in the general care landscape, which is documented by the National Dementia Strategy adopted in mid-2020.

In my research, the needs of people with dementia and their relatives relate to three major topics:

1. Individualization of treatment and care for people with dementia and their relatives. While dementia is a syndrome, treatment and care is individual. People vary due to comorbidities (accompanying illnesses), some live alone others do not, some are socially strongly integrated, understandings of health differ, goals in life etc. The more individual treatment and care is designed, the more effective it can be. That is my basic conviction and under this aspect I conduct scientific effectiveness and evaluation studies.
2. Availability, access and quality of care. This refers to “the other” side of the supply. In principle everything is there, but do people use it? What are conducive and hindering conditions? How does for example an offer in a rural area have to be equipped in order to be used? Like in a metropolitan area? There is not one model for all of Germany.
3. Relative burden and support. Most people are cared for at home. This is stressful and often the relatives suffer physically and psycologically. How can the supply system be changed in order to counter this, how can this be improved?

A core idea in my research is the participation of those involved in the research. I want to do research with effectiveness and impact on supply. For this it is important to work together with those affected. This applies to both patients and relatives, as well as providers. The needs of this group must be recognized, analyzed and (if they are not met) satisfied or implemented in intervention models. On the one hand, this improves the acceptance of interventions and, on the other hand, increases the likelihood that a sustainable improvement will occur.

I would like to implement this participatory approach with the help of the Alzheimer Research Prize 2020 from the Hans and Ilse-Breuer Foundation. I am planning a comprehensive needs analysis for general practitioners in private practice for the care of people with dementia. The resident general practitioner is usually the first point of contact for those affected and their relatives, has known these patients for a long time and has often built up a relationship of trust. He is therefore in the front row in the supply and can implement concepts. For this, however, it is necessary to know what the needs of the doctors are, what they lack in care, where there are obstacles / barriers or unused opportunities. I would like to collect and analyze this with the help of the prize money and ultimately integrate it into the development of further concepts.

I hope that research geared to the needs of care will have a lasting effect on the implementation of scientific findings in routine and can optimize them. This benefits those affected, their relatives and their carers alike.

CV

Jochen René Thyrian was born on November 12, 1971 in Euskirchen. He studied psychology at the Julius Maximilians University of Würzburg and obtained his diploma in 1999. His diploma thesis was dedicated to the subject of emotionality after a traumatic brain injury. First, he worked as a neuropsychologist in the early rehabilitation of neurological patients before moving to the University of Greifswald for the purpose of doing his doctorate. In 2005 he was awarded a Dr. rer. med. PhD. Already in addiction research, he carried out intervention studies, the main focus of which was the effectiveness at the population level. In 2011 he received his habilitation at the University of Greifswald on the subject of population effectiveness of preventive measures and received the venia legendi in epidemiology and social medicine. Since 2010 he has been researching at the German Center for Neurodegenerative Diseases in the field of interventional health services research. A working group was established as part of a tenure track process, which was consolidated in 2018 after a successful evaluation. He is a co-opted board member of the German Alzheimer's Society and is active in various scientific advisory boards. René Thyrian is married and has two sons. He spends his free time with his family, is a passionate motorcycle driver and sings as a tenor in the choir.

Forschungspreis 2017 – Prof. Steffi G. Riedel-Heller

Prof. Steffi G. Riedel-Heller, MPH

Director of the Institute of Social Medicine, Occupational Medicine and Public Health (ISAP) of the Faculty of the Medical University of Leipzig

Steffi G. Riedel-Heller studied medicine at the Karl Marx University in Leipzig and public health at the Johns Hopkins University in Baltimore, USA. She wrote her habilitation on the epidemiology of dementia. From 2004 to 2010 she was Professor of Public Health at the Leipzig University Hospital and has been Professor of Social Medicine at the Leipzig University Hospital since 2010. In addition, she is an elected member of the Faculty Council and Senate of the University of Leipzig as well as the chair of the doctoral committee of the Medical Faculty of the University of Leipzig. She is a board member of the German Society for Psychiatry and Psychotherapy, Psychosomatics and Neurology (DGPPN) and a member of numerous specialist societies (including the German Society for Epidemiology, the German Society for Social Medicine and Prevention).

Vortrag (PDF-Dokument, 3.3 MB) vom 11. Mai 2019 im StattHaus Offenbach der Hans und Ilse Breuer-Stiftung
"Geistig fit ins Alter - Was Sie zur Demenzprävention beitragen können"

Research Award 2016 – Prof. Heiko Braak

Prof. Heiko Braak

Forschungsergebnis

Tau seeding and strains in brains staged for Alzheimer disease-related neurofibrillary changes

We are interested in pathological tau protein seeding and different tau protein conformers (“strains”) in autopsy brains staged for Alzheimer’s disease-related lesions. Highly sensitive seeding assays make it possible to detect the presence of pathological tau seeding even before tau aggregates can be visualized in AT8-immunoreactions. The identification of different tau conformers can provide clues about the pathogenicity of the tau protein and to what extent they may influence a more or less aggressive disease course. Taken together, both aspects should make it possible to determine whether cases designated as putative “primary age-related non-AD tauopathy” (PART) rather than AD are in continuum with or are separate from the pathological process underlying Alzheimer’s disease. In addition, we are interested in the ontogenesis (from early childhood onwards) of the pre-α layer (lamina II) in the human entorhinal cortex and the subsequent development of the AD-related lesions and their effects there as well as in the perforant pathway. The entorhinal pre-α layer is the first site to develop pathological tau changes in the cerebral cortex during AD and, by end-stage disease, the destruction of layer pre-α (and layer pri-α) disconnects the entorhinal cortex from the hippocampal formation and both from the neocortex. With CLARITY, we hope to make possible 3D-imaging of the pre- and post-synaptic densities of layer pre-α dendrites to identify the loss of connectivities between neocortex and allocortex during AD.

Interview mit Prof. Heiko Braak

Forschungspreis 2014 – Prof. Stefan Lichtenthaler

Prof. Stefan Lichtenthaler

Forschungsergebnis

„Medikamenten-Entwicklung für die Alzheimer Krankheit kann effizienter und sicherer gemacht werden“

An der Alzheimer Krankheit sind in Deutschland über 1 Million Menschen erkrankt. In der Alzheimer Forschung arbeiten wir mit Hochdruck daran, sichere und effiziente Medikamente zur Behandlung der Ursachen dieser Krankheit zu entwickeln. Zielmoleküle zur Medikamenten-Entwicklung sind unter anderem bestimmte Enzyme im Gehirn, die als molekulare Scheren fungieren und das Alzheimer Eiweiß in kleinere Stücke schneiden. Eines dieser Bruchstücke kann Verklumpungen bilden, die die Nervenzellen im Gehirn schädigen und letztlich zur Alzheimer Krankheit führen. Mit Hilfe des Breuer Preises haben wir neue analytische Methoden entwickelt, mit denen wir dann herausgefunden haben, dass diese molekularen Scheren nicht nur das Alzheimer Eiweiß schneiden, sondern auch weitere Eiweiße im Gehirn. Das bedeutet aber, dass eine medikamentöse Hemmung der molekularen Scheren möglicherweise zu unerwünschten Nebenwirkungen führen könnte, da die anderen Eiweiße auch nicht mehr geschnitten werden. Um solche Nebenwirkungen zu verhindern, haben wir herausgefunden, welche der anderen Eiweiße besonders wichtig im Gehirn sind. Nun entwickeln wir diagnostische Nachweismethoden, um genau diese Eiweiße und ihre Bruchstücke in der Gehirnflüssigkeit und im Blut einfach zu messen. Damit wird es künftig möglich sein, für jeden Patienten die geeignete Dosis des Medikaments zu finden, um eine maximale Effizienz bei gleichzeitig minimalen Nebenwirkungen zu erreichen. Zusammenfassend hilft uns der Breuer Preis, die Medikamenten-Entwicklung für die Alzheimer Krankheit effizienter und sicherer zu machen.

CV

Stefan F. Lichtenthaler studied chemistry at the universities of Karlsruhe, Montpellier (France) and Heidelberg. He then did his doctorate at the Center for Molecular Biology at Heidelberg University. After a postdoctoral stay at Harvard University (USA), he became a junior research group leader at the Ludwig Maximilians University of Munich (LMU), where he qualified as a professor in biochemistry. In 2009 he became head of department at the newly founded German Center for Neurodegenerative Diseases (DZNE). Since 2012 he has held the chair for neuroproteomics at the Technical University of Munich (TUM) and the DZNE Munich.

Zu den ausgewählten Publikationen von Prof. Stefan Lichtenthaler »

Forschungspreis 2014 – Prof. Mikael Simons

Prof. Mikael Simons

Forschungsergebnis

„Tieferes Verständnis der Funktion von Phagozyten im Alter“

Wir interessieren uns für die Funktion von Phagozyten im Gehirn. Phagozyten sind wichtiger Bestandteil der angeborenen Immunantwort und für die Vernichtung von eingedrungen Pathogenen, aber auch von körpereigenen Material wie, amyloide Plaques, zuständig. Der Einschluss der Partikel erfolgt über die Bildung von Phagosomen, die nach Aufnahme der Partikel mit speziellen Vesikeln, den Lysosomen, verschmelzen. Um die Funktion dieser Zellen zu untersuchen, injizieren wir ein Toxin in die weiße Substanz des Gehirns, um die Myelinscheide lokal zu schädigen. Das beschädigte Myelin wird dann von Phagozyten in das Innere der Zelle aufgenommen und verdaut. Führt man jedoch dieses Experiment bei älteren Tieren durch findet man eine Anhäufung von unverdauten Resten in der Zelle. Bei den älteren Tieren kommt es in den Phagozyten zu Ablagerungen von Cholesterin in den Lysosomen. Das Cholesterin stammt aus den Myelinscheiden, die zu einem hohen Anteil aus Cholesterin bestehen. Die Anhäufung von Cholesterin löst nach einiger Zeit eine Entzündungsreaktion aus. Zur den Ablagerungen kommt es, weil die Phagozyten nicht in der Lage sind, Choleste­rinmoleküle abzubauen. Das überschüssige Cholesterin muss durch Lipoproteine abtransportiert werden. Im Gehirn wird diese Aufgabe in erster Linie von Apolipo­protein E übernommen. Diese Ergebnisse sind für das Verständnis der Funktion von Phagozyten im Alter relevant.

CV

Mikael Simons studied medicine in Heidelberg. He received his doctorate in 1998 with a double-award-winning dissertation on the molecular mechanisms of Alzheimer‘s disease, which was developed at the Center for Molecular Biology in Heidelberg. As a postdoctoral fellow and recipient of a grant from the German Research Foundation, he worked at the Institute for Neurobiology at Heidelberg University. From 2000 to 2004 he was an assistant doctor at the Neurological University Clinic in Tübingen. In 2004 he became a specialist in neurology and completed his habilitation in 2005 at the University of Göttingen. In 2007 he took over the management of the multiple sclerosis outpatient department at the Department of Neurology, University of Göttingen. In 2008 he became group leader at the Max Planck Institute for Experimental Medicine and was appointed to the Department of Neurology at the University of Göttingen in 2008 with a W3 Heisenberg professorship.

Forschungspreis 2013 – Prof. Dieter Edbauer

Prof. Dieter Edbauer

Professor of Translational Neurobiochemistry, DZNE & Ludwig-Maximilians-Universität München
Gruppenleiter der Helmholtz-Nachwuchsgruppe
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)

Forschungsergebnis

"Toxizität der Dipeptid-Repeat (DPR) Proteine"

Bei erstaunlich viele Patienten die unter den Erkrankungen Frontotemporaler Demenz (FTD) und Amyotropher Lateralsklerose (ALS) leiden finden sich weitere Betroffene in der Familie. Durch genetische Untersuchungen in diesen Familien konnten zahlreiche ursächliche Mutationen identifiziert werden. Am häufigsten ist eine Mutation in einem kaum charakterisierten Gen mit dem kryptischen NamenC9orf72, die ca. 5-10% aller ALS/FTD Patienten betrifft. Patienten mit dieser Mutation weisen eine massive Verlängerung von mehreren hundert oder sogar tausend Wiederholungen einer (GGGGCC)_n Sequenz im nicht-kodierenden Teil desC9orf72 Gens auf. Wir haben entdeckt, dass die verlängerte (GGGGCC)_n Sequenz unerwartet in allen Leserahmen in aggregierende Proteine übersetzt wird. Dabei entstehen fünf sogenannte Dipeptid-Repeat (DPR) Proteine (Mori et al, Science 2013), die zahlreiche Ablagerungen in den Nervenzellen der Patienten bilden. Die entscheidenden Fragen sind nun, welche Rolle die DPR Proteine bei der Krankheitsentstehung spielen und wie toxische Effekte medikamentös behandelt werden können.

Durch die Unterstützung des Forschungspreises der Hans und Ilse Breuer-Stiftung konnten wir die toxische Wirkung der DPR Proteine in Zellkultur und in Mausmodellen genauer untersuchen. Dabei interessierte uns insbesondere die Verbindung von DPR Proteinen mit den zytoplasmatischen TDP-43 Ablagerungen, weil diese Aggregate auch bei ALS/FTD Patienten ohneC9orf72 Mutation beobachtet werden und vermutlich eine direkte Ursache des Zelltods sind. Wir haben entdeckt, dass DPR Proteine den normalen Import von TDP-43 in den Zellkern stören und so dessen Aggregation im Zytoplasma begünstigen (Khosravi et al., Hum Mol Genet 2017). Weiterhin konnten wir eine Interaktion zwischen zwei der DPR Proteine und Ribosomen sowie anderen RNA-bindenden Proteinen nachweisen. Dadurch wird vermutlich die gesamte zelluläre Translation chronisch gestört und die Neurodegeneration mit ausgelöst (Hartmann et al., Life Sci Alliance 2018). In Zellkultur konnten wir zeigen, dass monoklonale Antikörper die Aggregation und Zell-zu-Zell Übertragung von DPR Proteinen hemmen (Zhou et al., EMBO Mol Med 2017). Jetzt testen wir die Wirksamkeit dieser dieses Therapieansatzes in einem transgenen Mausmodell fürC9orf72 ALS/FTD, dass wir zuvor etabliert und näher charakterisieren haben (Schludi et al., Acta Neuropathol 2017).

Mit einem Teil des Preisgeldes haben wir eine 96-Kanal Pipette und andere Geräte zur Hochdurchsatz-Analyse von biologischen Proben angeschafft. So konnten wir ein halb-automatisches Verfahren entwickeln, um in Stammzellen ausC9orf72 Patienten hunderte Medikamente gleichzeitig auf ihre Wirksamkeit zu untersuchen. Zunächst testen wir eine Sammlung bereits für andere Krankheiten zugelassener Medikamente. Sollte sich hierbei ein bereits bekanntes Medikament inC9orf72 Zellen als wirksam erweisen, wäre das ein vielversprechender Therapieansatz mit weniger Hürden für eine baldige klinische Studie in Patienten.

CV

Dieter Edbauer studied medicine in Munich (1994-2000). In his doctoral thesis with Prof. M. Hallek at the gene center of the Ludwig Maximilians University (LMU), he dealt with DNA vaccines against lymphomas (1998-2001). As a doctor in internship (AiP), later as a postdoc and then as a research assistant, he moved to the Adolf Butenandt Institute at LMU, where he and Prof. C. Haass researched the biochemical mechanisms of Alzheimer‘s disease (2001-2004). As the climax of the work, a key enzyme in Alzheimer‘s disease, the so-called gamma secretase, was molecularly defined for the first time. This was followed by a stay abroad at the Massachusetts Institute of Technology in the laboratory of Prof. M. Sheng (2004-2009). The work focused on signal transduction and cell biology in neurons in connection with Alzheimer‘s and Fragile X Syndrome, a hereditary form of mental retardation. In November 2009, Prof. Edbauer returned to the newly founded DZNE in Munich as the first Helmholtz Young Investigator Group Leader. By analyzing the molecular mechanisms of synaptic malfunction in Alzheimer‘s disease, new therapeutic approaches are to be identified. 

Zu den ausgewählten Publikationen von Prof. Edbauer »

Forschungspreis 2013 – Prof. Michael T. Heneka

Prof. Michael T. Heneka

Forschungsergebnis

„Identifikation neuer Angriffspunkte für zukünftige verlaufsmodifizierte Behandlungsansätze“

Bei zahlreichen neurodegenerativen Erkrankungen kristallisiert sich die Beteiligung inflammatorischer Mechanismen zunehmend als wesentliche Komponente der Krankheitsentstehung und -entwicklung heraus. Mikrogliazellen als Repräsentanten des angeborenen Immunsystems im ZNS werden dabei durch Aggregate aus fehlgefalteten Proteinen oder Nukleinsäuren simuliert. Aus deren neuroprotektiver und homöostatischer Wirkung unter physiologischen Bedingungen entsteht durch diese Aktivierung ein chronischer Entzündungsprozess, der über pro-inflammatorische Zytokine zum neuronalen Zelluntergang beiträgt. Im Fokus unserer Arbeiten steht das NLRP3 Inflammasom. Dabei handelt es sich um einen Signalweg, der am Beginn der Aktivierung des angeborenen Immunsystems steht und wesentlich die Entwicklung einer chronischen Entzündung im Gehirn mitbestimmt. Zunächst wiesen wir die Aktivierung dieses entzündlichen Signalmechanismus im Gehirn von Alzheimer Patienten nach mit immunhistochemischen und biochemischen Methoden nach. Interessanterweise war eine starke Aktivierung des NLRP3 Immunmechanismus bereits bei Patienten mit milder kognitiver Einschränkung (MCI) nachweisbar, was darauf hindeutet, dass die beobachtete Aktivierung bereits vor dem Erreichen des Demenzstadiums stattfindet. In einem nächsten Schritt konnten wir zeigen, dass die genetische Blockade des NLRP3 Inflammasoms in einem Mausmodell der Alzheimer Krankheit neuroprotektiv wirkt. Die Blockade des NLRP3 Inflammasoms verhinderte die entzündliche Aktivierung der Mikroglia, die daraufhin einen verbesserten Abbau der Amyloid Ablagerungen im Gehirn der Mäuse zeigte. Besonders wichtig war der Befund, dass die reduzierte Entzündungsreaktion und der verbesserte Abbau der Amyloid-Ablagerungen einen Schutz synaptischer Verbindungen sowie eine deutlich verbesserte hippokampale Funktion zur Folge hatte.

Da Neuroinflammation schon früh und vor dem Eintreten klinischer Symptome der Alzheimer Krankheit einsetzt, sind die beteiligten Mechanismen attraktive Angriffspunkte für zukünftige  verlaufsmodifizierende Behandlungsansätze.

CV

Prof. Heneka is the head neurologist at the interdisciplinary Clinical Treatment and Research Center (KBFZ) for neurodegenerative diseases at the University Hospital Bonn.

Michael Heneka graduated from the University of Tübingen with a degree in human medicine in 1996. He received his PhD in 1998 at the Institute for Pharmacology and Toxicology on the subject of "The effect of polymerized hemoglobin on cardiovascular and renal parameters in septic shock". He then worked as a postdoc at the laboratory of Prof. D.L. Feinstein, University of Illinois at Chicago, Chicago, USA. In 2002 he became a specialist in neurology, and in 2003 he completed his habilitation in neurology at the University of Bonn on the subject of "Inflammatory mechanisms of Alzheimer's disease: characterization and development of therapeutic strategies"

After a fellowship in the Department of Neurosciences, Case Western Reserve University, Cleveland, USA in the laboratory of Prof. K. Herrup and Prof. G.E. Landreth returned to Bonn in 2004 and initially worked as a senior physician at the clinic and polyclinic for neurology.

In the same year he was offered a professorship (C3) for molecular neurology at the Westfälische Wilhelms-Universität (WWU) Münster, where he worked from 2004 to 2008. During this time he headed the Department of Molecular Neurology and the dementia clinic at the MS University Hospital. In 2008 Michael Heneka was appointed university professor (W3) for clinical neurosciences at the Rheinische Friedrich-Wilhelms-Universität Bonn. Since 2010, Prof. Heneka has been the neurological director of the joint neurological-psychiatric memory clinic of the Clinics for Psychiatry and Neurology (Clinical Treatment and Research Center, KBFZ), University Hospital Bonn.

In addition to his research, assessment and teaching activities, Prof. Heneka is head of the clinical research group 177 (DFG), board member of the BMBF competence network "Degenerative Dementia" (KNDD) and member of the Bonfor commission. He is also the organizer of the “Venusberg Meeting on Neuroinflammation”, which takes place every 2 years.

In 2011 he received the Christa Lorenz Prize for ALS research.

Zu den ausgewählten Publikationen von Prof. Michael T. Heneka »

Forschungspreis 2012 – Prof. Thomas Misgeld

Prof. Thomas Misgeld

Kurzbericht zur Mittelverwendung

"Nachweis frühzeitiger Transportstörungen bei degenerativen Erkrankungen der Nervenzellen"

Viele Erkrankungen des Gehirns und der Nervenzellen, einschließlich der Alzheimer’schen Erkrankung, sind durch das Absterben von Nervenzellen gekennzeichnet. Da dieses Absterben unumkehrbar ist, ist es ein zentrales Anliegen der Forschung im Bereich dieser neurodegenerativen Erkrankungen, zu verstehen, warum Nervenzellen so verletzlich sind. Ein Grund liegt in der ungewöhnlichen Form dieser Zellen: Ein winziger Zellkörper versorgt einen riesigen Zellfortsatz mit Bausteinen und Nährstoffen – dieser Zellfortsatz, das Axon, weißt häufig das hundert- bis tausendfache an Länge und Volumen auf. Zur Erhaltung des Axons haben Nervenzellen ein komplexes Transportsystem entwickelt, dass es ihnen unter normalen Bedingungen erlaubt, diese Versorgung zu sichern. Unter Erkrankungsbedingungen allerdings, gerät dieses System aus der Balance – und der Prozess des Absterbens beginnt. Mit Unterstützung der Breuer-Stiftung entwickelt mein Labor Methoden, diese Versorgungs- und Transportvorgänge in lebenden Zellen und Tiermodellen zu studieren. Dafür machen wir die Zellbausteine mittels genetischer Techniken sichtbar (z. B. in dem wir leuchtende Eiweißstoffe einbringen) und beobachten ihr Bewegungsmuster im Kontext verschiedener neurologischer Krankheitsmodelle mit modernen Mikroskopieansätzen. Zum Beispiel haben wir zeigen können, dass es bei Modellen von degenerativen Erkrankungen der Nervenzellen, die unsere Gliedmaßen bewegen, oder bei Modellen der Multiplen Sklerose, einer entzündlichen Erkrankung des Nervensystems, früh zu Transportstörungen kommt. Wir konnten auch beweisen, dass ähnliche Erscheinungen in streng lokaler Form auch als Teil der normalen Entwicklung dieser Nervenzellen auftreten. Dank der Hilfe der Breuer-Stiftung, ist dieser Forschungsansatz nun der Kern eines umfangreichen Forschungsprogramms im Bereiche degenerativer und entzündlicher Erkrankungen des Nervensystems.

Lebenslauf

Name	Prof. Thomas Misgeld
Geburtsdatum	30.08.1971
1991-1998	Medizinstudium, Technische Universität München
1993 - 1999	Doktorarbeit, Abteilung für Neuroimmunologie, Max-Planck-Institut für Neurobiologie, Martinsried
2000 - 2006	Post-Doc, Washington University in St. Louis und Harvard University, Cambridge
2006 - 2009	Sofja-Kovalevskaja-Nachwuchsgruppenleiter, Institut für Neurowissenschaften, Technische Universität München
seit 2009	Professor (W3) für Biomolekulare Sensoren und Fellow, TUM-Institute for Advanced Study, Technische Universität München
seit 2012	Co-Sprecher, DFG-Exzellenzcluster Munich Cluster for Systems Neurology (SyNergy)
seit 2012	Assoziiertes Mitglied, Deutsches Zentrum für Neurodegenerative Erkrankungen, München (DZNE)

Zu ausgewählten Publikationen von Prof. Thomas Misgeld »

Forschungspreis 2012 – Prof. Boris Schmidt

Prof. rer. nat Boris Schmidt

 

 

Forschungsergebnis

"Vereinfachte Diagnostik durch Markierung (Visualisierung) von Amyloid- und Tau-Ablagerungen“

Die Aggregate von Amyloid β und Tau-Protein sind die Kennzeichen der Alzheimerschen Krankheit. Die Verhinderung bzw. Äuflösung dieser Protein-Ansammlungen wird in klinischen Studien untersucht. Der Therapieerfolg derartiger Studien kann z.Z. nur durch die Kontrolle der kognitiven Leistungen der Patienten erfolgen, denn die eindeutige Diagnose einer Alzheimerschen Erkrankung erfolgt durch postmortale, histologische Diagnose am Gehirngewebe. Die fehlende Diagnostik eines relevanten Biomarkers an lebenden Patienten bedingt hohe Fallzahlen und mehrjährige Studiendauern und behindert dadurch die Therapieentwicklung. Ziel des durch die Hans-und-Ilse-Breuer-Stiftung geförderten Projektes war die rationale Entwicklung molekularer Sonden für diese Amyloid β− und Tau-Protein-Aggregate für die Untersuchung der Retina bei Morbus Alzheimer.

Die zu entwickelnden molekularen Sonden mussten bestimmte physikochemische Eigenschaften aufweisen, die eine hinreichende Fluoreszenzdiagnostik am Auge oder am Riechepithel mit geringem Signal-Rausch-Verhältnis ermöglichen. Weiterhin müssen diese Sonden eine Selektivität zu Alzheimer-assoziierten Proteinaggregaten aufweisen, aber nicht an ähnliche Aggregate anderer Proteine binden, um die notwendige diagnostische Differenzierung zu gewährleisten. Unter Verwendung der Struktur-Liganden-Affinitätsbeziehungen von Amyloid β− und Tau-Liganden wurden neue Fluorophore aus privilegierten Substanzklassen synthetisiert, die am Aβ bzw. Tau-PHF binden. Diese fluoreszenten Proben wurden histologisch gegen etablierte immunhistochemische Verfahren an Gehirngewebe von Alzheimer-Patienten evaluiert und anschließend in zellfreien Assays auf Proteinaffinität und ihre Fluoreszenzeigenschaft in Gegenwart der Zielproteine untersucht. In parallel durchgeführten Assays wurden die Zellgängigkeit, Lokalisation und die Toxizität der Substanzen analysiert. Es konnten schließlich zwei Substanzen identifiziert werden, die im Mausmodell eine Hirngängigkeit zeigen und Amyloid--Ablagerungen markieren. Mit einer dieser Substanzen konnten diese Ablagerungen auch in vivo (Mausmodell) visualisiert werden. Die Evaluation der Farbstoffe als Marker für Proteinablagerungen im menschlichen Riechepithel, die eine vereinfachte Diagnostik ermöglichen, dauert an.

 

Lebenslauf

Name	Prof. rer. nat Boris Schmidt
Geburtsort	San Fernando/Trinidad & Tobago
Geburtsdatum	20.09.1962
1991	Promotion zum Dr. rer. nat. (summa cum laude), Universität Hannover
1991 - 1992	Gastlehrer und -forscher an der Universität Uppsala, Biomedicinska Centrum, Professor A. Hallberg, PhD. Blutdruckregulierende Peptidmimetika
1992 - 1993	DFG-Postdoktorandenstipendium: Scripps Research Institute, La Jolla, USA, Prof. K. B. Sharpless, Nobelpreisträger 2001
1994	Stipendium der Universität Uppsala, Biomedicinska Centrum, Inst. för Organisk farmaceutisk Kemi, Peptidmimetika und enantioselektive Reagenzien
1998	Habilitation -Universität Hannover, Institut für Organische Chemie
1997 - 1999	Koordinator Asbestsanierung Institut für Organische Chemie, U.-Hannover
1999 - 2002	Novartis Pharma AG, Basel, Alzheimer Amyloid ß Inhibition, Parkinson
1994-99, 2005 - heute	Mitglied im Fachbereichsrat
1989-01, 1994-99, 2002 - heute	Institutsrat
2002 - 2006	Koordination und Modularisierung der Lehramtsstudiengänge
2004 - 2006	Leitung Reform der B.Ed. und M.Ed.-Studiengänge Chemietechnik
2005 - 2006	Koordination und Modularisierung B.Ed/M.Ed. Körperpflege
2004 - heute	Mitglied in 7 Berufungskommissionen
2011 - heute	Mitglied der Ethikkommission der TU Darmstadt
2012 - heute	Mitglied des Haushaltsausschuß des FB Chemie

Zu ausgewählten aktuellen Publikationen von Prof. rer. nat Boris Schmidt »

Forschungspreis 2011 – Prof. Manuela Neumann

Prof. Manuela Neumann

Forschungsergebnis

"Neue und international verwendete molekulare Klassifikation der frontotemporalen Demenz"

Die frontotemporale Demenz (FTD) ist eine unheilbare Erkrankung, die nach der Alzheimer-Demenz die zweithäufigste Demenzform bei Patienten unter 65 Jahren darstellt. Im Vordergrund steht hierbei eine starke Veränderung der Persönlichkeit und Beeinträchtigung des sozialen Verhaltens verursacht durch einen Zelltod bevorzugt in frontalen und temporalen Gehirnbereichen. Die amytrophe Latersklerose (ALS) ist die häufigste neurodegenerative Erkrankung des motorischen Nervensystems und geht vorrangig mit Muskelschwäche bis hin zur Atemlähmung einher. Beide Erkrankungen haben auf den ersten Blick zunächst wenig Gemeinsamkeiten, außer daß es bei beiden Erkrankungen zu krankhaften Eiweißverklumpungen (sog. Einschlusskörperchen) in Nervenzellen kommt. Mit den Entdeckungen der RNA-bindenden Proteine TDP-43 und FUS als verklumpende Eiweiße in den Einschlusskörperchen ​​sowohl bei FTD als auch ALS hat sich unser Verständnis zu Ursachen und Entstehung der FTD und ALS seit 2006 jedoch dramatisch verändert. Mit diesen Arbeiten wurde der Grundstein gelegt für die Erkenntnis, daß es sich bei FTD und ALS um Varianten eines klinisch-pathologischen Spektrums von Erkrankungen handelt, denen derselbe Pathomechanismus, nämlich eine Störung des RNA Metabolismus, zugrunde liegt (Neumann et al. Science 2006; Neumann et al. Brain 2009).

Durch die Unterstützung der Breuer-Stiftung konnten wir zum einen die Zusammensetzung dieser Einschlusskörperchen weiter entschlüsseln und die Liste der krankmachenden Eiweiße um TAF15, EWS und Transportin erweitern (Neumann et al. Acta Neuropathol 2012). Interessanterweise fanden sich trotz der oben genannten Gemeinsamkeiten auch wichtige Unterschiede in der Zusammensetzung der Einschlusskörperchen zwischen ALS und FTD, die von entscheidender Bedeutung zur weiteren Aufklärung der Ursachen für die Proteinverklumpung sind (Rademakers et al. Nat Rev Neurol 2012, Neumann Rev Neurol 2013). Weiterhin konnten wir die Konsequenzen von bestimmten Mutationen imFUS oderC9orf72 Gen bei der Entstehung von ALS und FTD charakterisieren (Waibel et al. Eur J Neurol 2012, Mackenzie et al, Acta Neuropathol 2013). Neben diesen Erkenntnissen, die zu einer neuen und international verwendeten molekularen Klassifikation der FTD und ALS geführt haben, lieferten die Arbeiten auch die Grundlage für die Entwicklung neuer FTD/ALS-Modellsysteme. Derartige Projekte sind sehr langfristig angelegt und kostspielig, so dass das Preisgeld der Breuerstiftung darüberhinaus essentiell für die Generierung neuer genetisch veränderter Mauslinien für TDP-43 und FUS in meinem Labor war. Diese Modelle erlauben uns nun die Funktionen dieser Proteine gezielt im Gehirn zu untersuchen um somit weitere Erkenntnisse zu den Krankheitsmechanismen bei FTD und ALS zu gewinnen.

Lebenslauf

Name	Prof. Manuela Neumann
Geburtsdatum	15. Januar 1969
seit 2012	Professorin (W3) für Neuropathologie, Universität Tübingen, Ärztliche Direktorin, Abteilung Neuropathologie, Universitätsklinikum Tübingen, Arbeitsgruppenleiter „Molekulare Neuropathologie
2008-2012	Assistenzprofessorin für Experimentelle Neuropathologie sowie Oberärztin am Institut für Neuropathologie, Universität Zürich
2006-2008	Senior Scientist und Gruppenleiterin am Zentrum für Neuropathologie und Prionforschung der Ludwig-Maximilians-Universität München
2006	Habilitation zu „Molecular Neuropathology of Synucleinopathies and Tauopathies”
2005-2006	Gastforscherin am Center for Neurodegenerative Disease Research, Hospital of University of Pennsylvania, Philadelphia, USA
2004	Fachärztin in Neuropathologie
1999-2004	Ausbildung zur Fachärztin
1998	Promotion auf dem Gebiet der Prionen an der Georg-August-Universität Göttingen

Zu ausgewählten Publikationen von Prof. Manuela Neumann »

Research Award 2010 – Prof. Paul Saftig

 

Prof. Paul Saftig

"The physiological function of the Alzheimer’s disease relevant secretases"

 

Project Description

Curriculum vitae

Name	Prof. Paul Saftig
Place of Birth	Hennef (Sieg)
Date of Birth	02.09.1962
since 2001	Professor (C3) und Direktor des Biochemischen Instituts der Christian-Albrechts-Universität-Kiel
2000	Habilitation in Biochemie, Universität Göttingen
1994-2000	Research Assistant an der Universität Göttingen
1991-1994	Doktorarbeit an der Universität Göttingen; Biochemie II; Prof. K. von Figura: "In vivo functions of lysosomal proteins"
1989-1990	Diplomarbeit am Institut für Medizinische Microbiologie (Universität Göttingen), Prof. W. Büttner
1984-1989	Studium der Biologie an den Universitäten Bonn und East Anglia, Norwich (Great Britain)

 

Selected Publications of Prof. Paul Saftigg »

Special Award 2010 (financed by third-party funds) – Prof. Lawrence Rajendran

Prof. Lawrence Rajendran

 

"Membrane trafficking and targeting in Alzheimer’s disease"

 

Research Result

The accumulation of beta-Amyloid (Ab) aggregates within the brain plays a central role in the pathology of Alzheimer’s disease. Ab peptides are generated from a larger precursor molecule, the amyloid precursor protein (APP), which needs to be cleaved by two secretases, first by the b-secretase protein and then by the g-secretase complex. All of these proteins are membrane associated. They are found mainly at the plasma membrane of the cell and at intracellular membrane compartments, so-called endosomes, that are formed through invagination of the plasma membrane. The intracellular trafficking of membranes and their associated proteins is tightly regulated. One important group of membrane trafficking regulators are Rab proteins.

We wanted to study in detail which Rab proteins take part in the regulation of membrane trafficking events that affect the production of Ab peptides so as to better understand the subcellular events that contribute to Alzheimer’s disease.  To do so, we performed a paired genetic screen in a cell culture system where we either used a technique called RNA interference to suppress the production of Rab proteins one by one, or we used so-called GTPase-activating proteins to render specific groups of Rab proteins inactive without altering their protein levels. Through this screen we identified several Rab proteins that significantly increased or decreased Ab levels. One of the strongest hits, the Rab11 protein, was found to promote Ab production by allowing the cell to recycle its b-secretase. The secretase is trafficked from endosomes back to the plasma membrane, thus escaping early degradation and given the chance to cleave additional APP molecules.

Having identified the key Rab proteins that regulate amyloid production, we then performed a similar membrane trafficking screen to study the role of Rab proteins in Ab clearance.  While production of Ab takes place almost exclusively in neurons, cellular clearance in the brain is mediated mainly by microglia. These macrophagic cells take up Ab from the extracellular space and can then degrade it intracellularly.  We identified several Rab proteins that altered the capacity of microglia to clear Ab, e.g. Rab which was found to positively regulate the number and function of the microglia’s digestive organelles, thereby ensuring efficient intracellular amyloid clearance. What is intriguing is that Rab7 also seems to play a crucial role in the regulation of another key player in Alzheimer’s disease, the Tau protein. We found that a reduction of a key Rab GTPase in neurons resulted in more intracellular Tau and also in higher levels of a modified form of the protein that is typically seen in Alzheimer brains. Thus, Rab dependent membrane trafficking pathways appear to control two of the main etiological factors of the disease, that is Ab clearance and regulation of Tau.

 

Curriculum vitae

June 2009 – present	University of Zurich, Medical Faculty, Co-Director & Assistant Professor, Systems & Cell Biology of Neurodegeneration
Nov 2007 – June 2009	Max Planck Institute of Molecular Cell Biology and Genetics, Germany, Principal Investigator, Alzheimer Forschung Initiative project & BMBF-FORMAT project “Membrane intervention and systems biology approaches for AD therapy”
July 2003 –  Nov 2007	Max Planck Institute of Molecular Cell Biology and Genetics, Germany, Postdoctoral fellow with Kai Simons, M.D., Ph.D.
2003-2007	Postdoc Cell Biology and Neurosciences, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany (Cell biology of Alzheimer’s disease)
2001-2003	PhD Immunology (Natural Sciences), University of Konstanz, Konstanz, Germany. Thesis: Role of Membrane microdomains in Leukocyte polarity and signaling
1997-2000	Pre-PhD Molecular Biophysics, Indian Institute of Science,  Bangalore, India Folding of Lectins and artificial chaperone assisted folding of proteins
1995-1997	MSc Molecular Biology, University of Madras, Madras, India
1992-1995	BSc Biochemistry, University of Madras, Madras, India

Selected Publications of Prof. Lawrence Rajendran »

Special Award 2010 (financed by third-party funds) – Prof. Lars Bertram

Prof. Lars Bertram

 

 

Research Result

"Functional characterization of micro-RNA sequence variants" 

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population. Specific changes in a person's DNA sequence can either cause ("mutations") or increase the risk ("polymorphisms") for the disease in some individuals. The functional / pathogenetic correlate exerted by the latter type of variant often remains elusive despite otherwise compelling genetic evidence, e.g. the presence of genome-wide significant evidence of association with risk for disease. The overarching goal of the project funded by the Hans and Ilse Breuer-Stiftung was to explore the potential role of AD-associated DNA sequence variants on the function of micro-RNAs (miRNAs). MiRNAs are small RNA molecules that can bind to messenger-RNA (mRNA) and thereby regulate expression of the   encoded proteins. To achieve this goal, we applied a multi-pronged approach combining state-of-the-art bioinformatics and laboratory experiments. Overall, we systematically assessed a total of 22 different AD-associated polymorphisms on their potential to interfere with miRNA-regulated protein expression. In silico (i.e. bioinformatics) predictions highlighted eight SNP-miRNA-mRNA combinations that were followed up by in vitro (i.e. laboratory) experiments, including variant-specific luciferase reporter assays and miRNA-specific expression profiling in human brain samples. Overall, our data suggest that AD-associated SNPs in MS4A6A, FERMT2, and NUP160 could be exerting all or part of their pathogenetic effects via disturbing miRNA-to-mRNA binding and, thus, expression of the related proteins. The results of these experiments were presented at the 2013 “Alzheimer’s Association International Conference“ (AAIC) in Boston. Using a similar approach on genome-wide association study data on human memory performance, we could further show that miRNA-138 is a potential molecular regulator of human memory function (Schröder et al, 2014).

Since then, our group has intensified its efforts in miRNA research and was recently able to publish several papers in this domain (e.g. Schulz et al, 2018; Wohlers et al, 2018, Takousis et al, 2019). These latter projects would not have been possible without the work funded earlier by the Breuer-Foundation.

 

References:

Schröder J, Ansaloni S, Schilling M, Liu T, Radke J, Jaedicke M, Schjeide BM, Mashychev A, Tegeler C, Radbruch H, Papenberg G, Düzel S, Demuth I, Bucholtz N, Lindenberger U, Li SC, Steinhagen-Thiessen E, Lill CM, Bertram L. „MicroRNA-138 is a potential regulator of memory performance in humans.“ Front Hum Neurosci. 2014 Jul 11;8:501. doi: 10.3389/fnhum.2014.00501.

Schulz J, Takousis P, Wohlers I, Itua IOG, Dobricic V, Rücker G, Binder H, Middleton L, Ioannidis JPA, Perneczky R, Bertram L, Lill CM. „Meta-analyses identify differentially expressed micrornas in Parkinson's disease.“ Ann Neurol. 2019 Jun;85(6):835-851. doi: 10.1002/ana.25490.

Takousis P, Sadlon A, Schulz J, Wohlers I, Dobricic I, Middleton L, Lill CM, Perneczky R, Bertram L. “Differential expression of microRNAs in Alzheimer’s disease brain, blood and cerebrospinal fluid” Alzheimer’s & Dementia (in press)

Wohlers I, Schulz C, Kilpert F, Bertram L “Alzheimer’s disease risk SNPs show no strong effect on miRNA expression in human lymphoblastoid cell lines“ bioRxiv 367318; doi: https://doi.org/10.1101/367318

 

Curriculum vitae

Name	Dr. Lars Bertram
Place of Birth	Hamburg
Date of Birth	12.04.1970
since 2008	Gruppenleiter, Neuropsychiatrische Genetik Max-Planck-Institut für Molekulare Genetik, Berlin
	Associate Faculty, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA
2004-2008	Assistant Professor of Neurology, Harvard Medical School, Boston, MA, USA
2002-2008	Assistant in Genetics, Massachusetts General Hospital, Boston, MA, USA
2001-2004	Instructor in Neurology, Genetics and Aging Research Unit, Harvard Medical School, Boston, MA, USA
1999-2001	Postdoc, Genetics and Aging Research Unit, Harvard Medical School, Boston, MA, USA
1997-1999	Assistenzarzt, Klinik für Psychiatrie und Psychotherapie, Klinikum rechts der Isar, München
1994-1997	Dissertation, Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum
1990-1997	Studium der Humanmedizin, Ruhr-Universität Bochum, Universite-Louis-Pasteur, Strasbourg/Frankreich, Univerity of Iceland, Reykjavik/Island

Selected Publications of Dr. Lars Bertram »

Research Award 2010 – Prof. Melanie Meyer-Lühmann

Prof. Melanie Meyer-Lühmann

Project Description

A number of degenerative neurological and systemic diseases are characterized by the accumulation of specific proteins in tissues. In the nervous system, these proteopathies include Alzheimer's disease (AD) and Parkinson's disease (PD) among others. In order to provide a meaningful therapy, it is essential to understand the pathogenesis of these diseases, particularly in their early stages. Since some patients show clinical and pathological features of AD and PD, it has been speculated that both diseases share overlapping pathogenic pathways and might even influence each other. During the course of AD, neurons lose synapses and specifically dendritic spines. They also suffer from changes in neurite architecture such as curvature caused by senile plaques. Since synapses and neurites are very plastic structures, they have the potential to recover after treatments, giving hope for some functional recovery.

I have previously shown that intracerebral injection of A-beta-containing human or transgenic mouse brain extracts can induce cerebral A-beta-amyloidosis and associated pathology in young pre-depositing APP transgenic mice and that this amyloid induction is time and concentration dependent (Meyer-Luehmann et al., 2006). This induced amyloidosis can effectively be blocked when brain extracts are mixed with anti-A-beta antibodies or by A-beta-immunization of the host. Although standard immunohistological approaches are powerful, they only reveal a snapshot of information. Taking advantage of multiphoton imaging where neuronal processes, amyloid plaques and blood vessels can be observed simultaneously in the living mouse in real time, I was able to study the temporal relationship between plaque formation and the changes in local neuritic architecture. Imaging on a daily basis uncovered that plaques appear relatively suddenly, between one imaging session and the next, 24 hours later. After a plaque appears, progressive neuritic changes lead to increasingly curved, dysmorphic neurites over the next few days to weeks within the immediate vicinity of plaques (Meyer-Luehmann et al., 2008). These results suggest that plaque-related neuritic changes are a direct consequence of dense-cored plaque formation and therefore a later event in AD pathogenesis. Imaging techniques such as 2-Photon microscopy allow visualization and characterization of A-beta plaques and neuritic changes as well as paradigms for preventing or reversing the deposits and associated pathologies. An effective analysis of amyloid-beta clearance is therefore possible in the living mouse, where plaques can be observed before, during and after treatment. I have helped to develop imaging approaches that allow the observation of amyloid-beta deposits chronically in the brains of living, APP transgenic mice using multiphoton microscopy.
The objective of future studies is to promote the understanding of the kinetics of plaque formation and associated neuritic abnormalities as well as the mechanism involved in the induction of A-beta aggregation and propagation in vivo and to suggest treatments that will restore neuritic morphology. Specifically I suggest to characterize early stages of A-beta plaque formation and to visualize associated neuronal dysfunction. Furthermore I would like to test the hypothesis that beta-synuclein would interact with A-beta and that A-beta protein aggregation and deposition can be induced by beta-synuclein. Another project will test the idea that blocking A-beta synthesis will lead to a structural recovery of neurites.
The proposed studies will unequivocally give new insights not only into the kinetics of amyloid plaque formation but also into the associated neuronal dysfunction and therefore provide valuable information for therapeutic intervention.
 

1. Meyer-Luehmann, M. et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313, 1781-4 (2006).

2. Meyer-Luehmann, M. et al. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451, 720-4 (2008).

Curriculum vitae

Name	Dr. Melanie Meyer-Lühmann
Birth place	Lahr
Date of Birth	31.03.2007
since 2008	Independent group leader at the Adolf-Butenandt-Institut, Ludwig-Maximilians-University Munich, Germany
2005-2008	Postdoctoral fellow at the Massachusetts General Institute for Neurodegenerative Disease (MIND), Harvard Medical School, Boston, USA, with Prof. Bradley T. Hyman
2004	Postdoctoral fellow at the Hertie Institute of Clinical Brain Research, Tuebingen, Germany, with Prof. Mathias Jucker
2004	PhD in Neurobiology, grade: summa cum laude, University of Basel, Switzerland
2000-2004	PhD Thesis at the University of Basel, Switzerland with Prof. Mathias Jucker. Title: Experimental approaches to study cerebral amyloidosis in a transgenic mouse model of Alzheimer`s disease.
2000	M.S. (Diplom) in Biology, grade: very good, University of Freiburg, Germany
1999-2000	M.S. (Diplom) Thesis at the University of Michigan, Ann Arbor, USA with Prof. John Wayne Aldridge. Title: Extracellular recordings in the substantia nigra pars reticulate during normal grooming behavior in rats.
1993-1999	Undergraduate and graduate studies of Biology at the University of Freiburg, Germany

 

Selected Publications of Dr. Melanie Meyer-Lühmann »

Research Award 2009 – Prof. André Fischer

Prof. André Fischer

Project description

Targeting epigenetic gene-expression as a therapeutic strategy to treat age-associated memory impairment and Alzheimer’s disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although the etiology of sporadic AD is not well understood, age is the single most risk factor. Therefore, as life expectancies continue to rise, AD is becoming tragically common. Despite intensive studies no cure is yet available.
I hypothesize that a better understanding of age-associated memory impairment (AAMI) will help to elucidate the pathogenesis of AD and vice versa. Interestingly, several lines of evidence indicate that AAMI and AD are accompanied by the selective down-regulation of genes involved with synaptic function. The reason for this down-regulation is not well understood but our preliminary data point to the possibility that deregulation of epigenetic mechanisms could be a common feature in neurodegenerative diseases and may provide very suitable therapeutic target.
The two most studied epigenetic phenomena are DNA-methylation and Histone-tail modifications, which build up discrete patterns of chemical marks recognized and bound by other proteins. The acetylation of histones is regulated by histone-acetyl transferases (HAT) and histone-deacetylases (HDAC), that transfer or remove acetyl-groups on specific lysine residues on histone-tails, respectively.
Recent reports, including our data, have shown that inhibition of HDAC activity can attenuate neuronal cell death and improve memory function. To what extend deregulation of epigenetic processes is involved in the pathogenesis of AD is however not understood.
In this project I suggest to employ biochemical, epigenetic, pharmacological and behavioral experiments to investigate how changes in chromatin structure and epigenetic gene-expression contribute to the pathogenesis of AAMI and AD. The therapeutic potential of targeting chromatin-modifying enzymes directly will be analyzed by a combination of pharmacological and genetic approaches.

 

Curriculum vitae

Name	Dr. Andre Fischer
Place of Birth	Flensburg
Date of Birth	12.06.1974
since 2007	Independent Group leader at the European Neuroscience Institute Göttingen, Head of the Laboratory for Aging and Cognitive Diseases
since 2006	Elected Member of the ENI-Network of European Young Investigators
since 2006	Affiliate at Massachusetts Institute of Technology, Picower Center for Learning and Memory, Cambridge, Massachusetts, U.S.A.
2005-2006	Postdoctoral Research Fellow at Massachusetts Institute of Technology, Picower Center for Learning and Memory, Cambridge, Massachusetts, U.S.A. Prof. Li-Huei Tsai
2003-2006	Postdoctoral Research Fellow at Harvard Medical School, Department of Pathology, Boston, Massachusetts, U.S.A. Prof. Li-Huei Tsai
2002-2003	Postdoctoral Research fellow, Max Planck Institute for Experimental Medicine, Göttingen, Germany, Prof. Jelena Radulovic
2002	PhD, summa cum laude, Georg-August University Göttingen
1999-2000	Diploma Degree, Max Planck Institute for Experimental Medicine, University Göttingen

Selected Publications of Dr. Andre Fischer »

Research Award 2008 – Prof. Ulrike Mueller

Prof. Ulrike Mueller

Project description

1. Background and Introduction

Alzheimer´s disease (AD) ist the most common neurodegenerative disorder and is characterized by synaptic disfunction, neuronal loss and cognitive decline. The major lesions found in the brains of AD patients are neruofibrillary tangles and neuritic plaques that are mainly composed of the b-amyloid peptide (Ab) derived via proteolysis from the amyloid precursor protein APP. APP is a single pass transmembrane protein that is processed in two different ways: a-secretase cleaves APP within the Ab region, thereby precluding Ab formation and releasing the APPsa ectodomain; in the amyloidogenic pathway APP is sequentially cleaved by b- and g-secretase, leading to Ab formation.

Whereas the mechanisms governing Aβ generation have been intensely studied, the physiological role of APP and of its numerous proteolytic fragments and the question of whether a loss of these functions contributes to AD are still unknown.

1.1 Knockout mice with individual or combined gene deficiencies of APP-family proteins
Determining the in vivo functions of APP in mammals is complicated by the presence of two APP-related genes, APLP1 and APLP2. APP and APLPs share two conserved domains in the extracellular region (E1 and E2) and one in the cytoplasmic domain, whereas the the b-amyloid peptide is lacking in APLPs.

Thus, functional redundancy may compensate for the loss of essential gene functions, e.g. in knockout (KO) models. Indeed, by generating various KO mutants we could demonstrate that the extensive structural similarities between APP and APLPs are also reflected at the functional level (Anliker and Müller, 2006). Mice in which APP, APLP1, or APLP2 is inactivated are viable and APP KO mice revelaed reduced brain and body weight, reduced grip strength, altered locomotor activity, increased susceptibility to seizures and a defect in spatial learning and LTP.

In contrast to the viable single mutants, combined APLP2-/-APP-/- and APLP2-/-APLP1-/- double mutants die shortly after birth indicating that APP family proteins serve redundant functions that are essential for viability (Heber et al., 2000). Whereas the brains of double knockout animals exhibit no obvious morphological defects, triple mutants lacking the entire APP gene family showed cranial dyspalsias resembling human type II lissencephaly (Herms et al., 2004).

Within affected areas neuronal cells from the cortical plate migrated beyond their normal positions and protruded into the marginal zone and the subarachnoid space. Thus, APP/APLPs play a critical role in neuronal adhesion and positioning. This role in cell adhesion is also supported by data from a recent collaborative study demonstrating that APP family proteins form cis- and trans-dimers involved in cellular adhesion and may thus play a role in neuronal differentiation, synapse formation and function (Soba et al. 2005). Collectively, our data reveal an essential role for APP-family members in normal brain development and early postnatal survival.

Fig1: Frontal section of a triple KO mouse at E 17.5 exhibiting a prominent protrusion (P) of the cortical plate. It becomes apparent that ectopic neurons completely disrupt the cortical plate (CP); the neuro- blasts are shifted into the marginal zone (MZ). (adapted from Herms et al., 2004)

1.2 In vivo analysis of APP functional domains
Secondly, another level of functional diversity may result from the complex proteolytic processing of APP and its APLP homogues by several secretases leading to diverse extra- and intracellular APP/APLP fragments. As these secretases have become major targets of therapeutic intervention it is of primary importance to elucidate the physiological function(s) of APP/APLPs and their processing products, because alterations in the activity or concentration of these fragments might have physiological consequences in itself.

Ultimately we would like to elucidate the physiological relevance of APP processing and to understand the specific functions of the respective cleavage product for both physiology and pathophysiolog. To this end we recently started a reverse genetic analysis of APP functional domains. We replaced the endogenous APP locus by gene targeted alleles and generated two lines of knockin mice that exclusively express APP deletion variants corresponding either to the secreted APP ectodomain (APPsa) or to a C-terminal truncation lacking the YENPTY interaction motif (APPDCT15) (Ring et al., 2007). Interestingly, the DCT15-deletion resulted in reduced turnover of holoAPP, increased cell surface expression and largely reduced Aβ levels in brain, likely due to reduced processing in the endocytic pathway.

Most importantly, we demonstrated that in both APP knockin lines the expression of APP N-terminal domains either largely attenuated or completely rescued the prominent deficits of APP knockout mice, such as reductions in brain and body weight, grip strength deficits, alterations in circadian locomotor activity, exploratory activity, and the impairment in spatial learning and LTP. Taken together our data suggest that the APP C-terminus is dispensable and that APPsa is sufficient to mediate the physiological functions of APP assessed by these tests (Ring et al., 2007). Ongoing experiments will show whether APPsa might also be sufficient to rescue defects underlying the lethal phenotype of APP-/-APLP2-/- mutants.

2. Outline of planned projects

The prize will be used to support our ongoing and planned efforts aimed at understanding the physiological as well as the pathological role of APP family proteins for Alzheimer´s disease and aging. To this end we intend to answer the following questions:
· What are the gene specific functions of the individual family members within the nervous systems, in particular with regard to neuronal differentiation, synaptogenesis, synaptic function and plasticity, as well as for learning and memory?
· In as much are these functions redundant within the gene family?
· What is the physiological function of the different proteolytic fragments generated from APP/APLPs (holoAPP, APPs, AICD)?
· What is the specific role of these fragments for AD pathogenesis?
· Can we do structure/function analysis?
· Which signaling mechanisms are involved and which genetic and molecular interactions are mediating these functions?

To this end we intend to use a combination of genetic and biochemical/cell biological approaches:

2.1 Reverse genetics of APP function in mice: role of APP and its fragments in the developing and adult nervous system.
Our recent paper by Ring et al. (2007) suggested that APPsa seems to be sufficient to mediate the (postnatal) functions of APP (at least as assessed by the various tests used). It is also clear, however, that APLP2 (which is still expressed at normal levels in KI mice) might have masked functional deficits, that can only be fully assessed on an APLP2-deficient background.

In this regard it will be crucial to determine whether APPsa is also sufficient to rescue the perinatal lethality of APLP2-/-APP-/- double knockout (DKO) mice. We have therefore crossed both APP-KI mutant with APLP2-/-mice and generated APPsα-KI/APLP2-/- and APP∆CT-KI/APLP2-/- double knockin (DKI) mice. So far, only very few litters have been analyzed, but preliminary analysis showed that DKI mice are viable, have grossly reduced body weight and exhibit abnormal motor behaviors. To phenotype these mice we will conduct a detailed anatomical/morphological characterization of the brain cytoarchitecture, determine neuronal number and morphology, with particular emphasis on CNS structures prominently affected in Alzheimers disease, such as hippocampus and cortex. As APP/APLPs have been implicated in synaptogenesis at the neuromuscular junction as well as in the CNS we will study in adult mice the synaptic architecture within the hippocampus. In addition we will conduct in colaboration an electrophysiological analysis of CNS synapses (e.g. in cortex and hippocampus) and assess potential deficits in short term and long term synaptic plasticity.

These studies will be complemented by an in depth analysis of neuronal morphology (dendritic complexity, synapse number, spine density) of principal neurons of the hippocampus in hippocampal slice cultures from our various gene targeted mice. Moreover, we will conduct a detailed behavioral characterization focusing on motor behaviours, sensory behaviours, as well as learning and memory. The second focus will be to extend our analysis of APP functional domains and generate additional gene targeted mouse mutants to study other important functional motifs including APPsb and the highly conserved E1 and E2 domains.

2.2 Generation of tissue-specific and inducible knockout mice.
Secondly, we intend to rescue the early postnatal lethality of the respective double mutants, in an effort to study functions at later stages of development and in the adult animal. Presently, the cause of the early postnatal phenotype of combined APP/APLP double and triple mutants is still unknown, raising the question in which organ system(s) the major functional defect may reside. To clarify this issue it will be crucial to generate APP/APLP single and combined gene deficiencies in a tissue specific, e.g. neuron specific way. Using tissue specific and tamoxifen-inducible cre-mediated deletion of the APP (or APLP2) gene we intend to analyse proposed functions in different neuronal populations during development, postnatally and in the adult.

2.3 Role of APP-dependent gene expression for Alzheimer disease
The proteolytical processing of APP is very similar to that of Notch and AICD has been suggested to function as a transcriptional regulator. Nevertheless, the nature of the relevant target genes is still under debate (see e.g. Pardossi-Picard et al., 2005 and Hebert et al., 2006). Using a microarray based approach we recently identified differentially expressed genes using cells (e.g. APP/APLP-deficient versus APP-reconstituted MEFs) and tissue (e.g. cortex and hippocampus) derived from single and combined APP/APLP mutants.

Thus, we identified several molecular pathways in which APP/APLPs are involved. Current work is aimed at follow up analysis of several interesting candidate genes (including e.g. neurotransmitter receptors , cell adhesion molecules). In this context we are particularly interested to clarify whether these new target genes are directly regulated at the mRNA level via AICD acting in a Notch-like manner, or are more indirectly affected by the absence of APP-family proteins.

2.5 Identification of extracellular and intracellular interaction partners
APP has since long been hypothesized to function as a cell surface receptor and to transduce various signals and so far only few binding partners have been identified. However, the in vivo ligands of APP/APLPs have remained unknown. We therefore intend to identify and functionally characterize such ligands using various interaction screens such as proteomics, pull down, immunoprecipitation and memebrane-based yeast two-hybrid screens.

Curriculum vitae

Name	Ulrike Müller
Place of birth	München, Germany
Date of birth	10.04.1960
since 2005	Professor for Funktional Genomik, Institute for Pharmacy and molecular biotechnology, University of Heidelberg
1999	Habilitation in Molecularbiology, University of Zürich
1997-2004	Leader of the independent Neurogenetics research group (C3 for 5 years)
1991-1997	EMBO longterm fellow and independent research group leader, Institute for Molecular Biology, University of Zürich
1989-1991	Postdoc Medical School, University of Manchester, UK
1989	Dipl. rer. nat. Biochemistry and Molecular Biology, University of Munich
1985	Dipl. Chemistry, Universiy of Munich

Selected Publications of Prof. rer. nat. Ulrike Müller »

Sonderpreis 2008 (finanziert durch Drittmittel) – Prof. Ralf Baumeister

Prof. Ralf Baumeister

Projektbeschreibung

Titel des Projektes:"Ein systembiologischer Ansatz zum Verständnis von Alterung und neurodegenerative Erkrankungen"

 

Lebenslauf

Name	Prof. Ralf Baumeister
Geburtsort	Schwabach
Geburtsjahr	1961
2006	W3 Professur an der Biologischen Fakultät und gleichzeitig Professur am Zentrum für Biochemie und Molekulare Zellforschung der Medizinischen Fakultät, Universität Freiburg
2006	Ablehnung eines Rufs zum Direktor von CISBIC (Center for Integrative Systems Biology) an das Imperial College, London, England, und Chair in Systems Biology
seit 2005	Direktor des Zentrums für Biosystemanalyse (ZBSA) Freiburg
2003	Rufe an Universität Uppsala, Schweden, Universität Ulm abgelehnt.•    seit 2003 Professor (Ordinarius) für Bioinformatik und Molekulargenetik an der Universität Freiburg, Fakultät für Biologie
2000-2003	Professor für Stoffwechselbiochemie am Adolf-Butenandt-Institut der Medizinischen Fakultät, Universität München
1995-2000	Leiter Labor für Neurogenetik am Genzentrum, Universität München
1992-1995	Harvard Medical School, Boston, USA, Mass. General Hospital
1992	Promotion in Mikrobiologie und Biochemie (Erlangen, Forschungsaufenthalte am Karolinska Institut, Stockholm, Inst. für Kristallographie Berlin)

Zu ausgewählten Publikationen von Prof. Ralf Baumeister »

Special Award 2008 (financed by third-party funds) – Prof. Magdalena Götz

Prof. Magdalena Götz

Project description

Glial cells as source for new neurons in AD mouse models

The project will investigate the changes in glial cells in AD mouse models and examine the best neurogenic fate determinants to reactivate neurogenesis in the adult cerebral cortex of these mouse models.

 

Curriculum vitae

Name	Prof. Magdalena Götz
Date of birth	17.01.1962
since 2004	Chair of Physiological Genomics, Medical Faculty, LMU Munich, Germany
since 2004	Director (C4) Stem Cell Institute, GSF – seit 01.01.2008: Helmholtz Zentrum München, Neuherberg-Munich, Germany
1997-2003	Research group leader at the Max-Planck Institute of Neurobiology, Munich-Martinsried, Germany
2000	Habilitation (Zoology)
1997	Scientist at the Max-Planck Institute of biophysical Chemistry, Göttingen, Germany
1994-1996	Postdoctoral Scientist at SmithKline Beecham Harlow, U.K.
1993-1994	Postdoctoral fellow at the National Institute for Medical Research, London, U.K.
1992-1993	Postdoctoral fellow at the Friedrich-Miescher Institute of the Max-Planck Society, Tübingen, Germany
1992	PhD-Thesis (summa cum laude)
1989-1992	PhD at the Friedrich-Miescher Instituteof the Max-Planck Society, Tübingen, Germany
1989	Diplome of Biology, University of Tübingen, Germany

Selected Publications of Prof. Magdalena Götz »

Research Award 2007 – Prof. Eva-Maria Mandelkow

Prof. Eva-Maria Mandelkow

Project description

The Alzheimer disease is characterized by abnormal accumulations of proteins in the brain, the "amyloid plaques" and the "neurofibrillary tangles". They occur in brain regions that are important for learning and memory - this explains the cognitive deficits in Alzheimer disease.

The research in our lab focusses on the protein "Tau" which causes the formation of neurofibrillary tangles. We investigate the normal functions of Tau in nerve cells and the malfunctions related to disease. Tau proteins serve normally as stabilizers or "ties" for the microtubule "tracks" which are res- ponsible for transport of material up and down the long axonal extensions of neurons (for example cell organelles, synaptic vesicles, protein and RNA complexes).

These "cargoes" are pulled by "motor proteins" along the microtubules. The strength of Tau-microtubule binding is regulated by biochemical signals, such as phosphorylation. In Alzheimer disease the signal- ling mechanisms appear to be perturbed so that Tau detaches from the microtubules, the microtubule tracks fall apart and the transport system breaks down. At the same time the detached Tau protein be- gins to accumulate into "paired helical filaments" which then assemble into the neurofibrillary tangles that obstruct the interior space of the cells.

We are studying the signalling pathways of Tau, the responsible enzymes (protein kinases), and the consequences for transport within cells and for Tau protein aggregation. One approach is to synthesize the Tau proteins in bacteria in recombinant form, which allows specific modifications of their properties. We also introduce Tau into neuronal cells or into "transgenic" mice which serve as models for the toxicity of Tau in Alzheimer disease. We observe the formation of the anomalous paired helical filaments of Tau by biophysical methods and electron microscopy, and we can visualize the movement and distribution of Tau and cell organelles in real time by confocal fluorescence microscopy (see figure). One of the major goals is to identify substances which can correct the pathological behavior of Tau and thus allow the sur- vival of the nerve cells.

With these methods we characterized several protein kinases which can transform Tau protein into a state of pathological phosphorylation, notably the kinase family MARK which can detach Tau from micro- tubules. We showed that Tau can inhibit axonal transport by blocking the attachment of motor proteins to microtubules (see movie, blue axon). We developed several neuronal cell models and mouse models where the expression of Tau can be switched on and off, so that one can observe the toxic effects of Tau expression, phosphorylation, and aggregation separately.

By screening a library of 200,000 chemical compounds we have discovered a number of substances which are capable of preventing the aggre- gation of Tau protein. These substances are currently modi- fied and investigated in order to understand their mode of action in cells. The long-term goal is to de- velop strategies for prevention or therapy of Alz- heimer disease.

Figure legend: The movie shows nerve cells in culture with their growing cell processes (axons), as seen by confocal light microscopy. The red particles are mitochondria, the "power stations" of cells that generate chemical energy. The mitochondria move up and down the axons, pulled by motor proteins a- long microtubules (not visible here). One single axon expresses Tau protein labeled with a blue fluo- rescent marker (CFP). In this cell the movement of mitochondria is severely impaired.

For further information see: www.mpasmb-hamburg.mpg.de

 

Curriculum vitae

Name	Prof. Eva-Maria Mandelkow
since 1986	Max-Planck-Workgroup for Structural Molecularbiology, Hamburg (Groupleader, C3)
1976-1985	Max-Planck-Institute for medical research, Heidelberg (Scientic)
1973	Dr. in Biochemistry at the Max-Planck-Inst. for med. research, Heidelberg
1974-1975	Brandeis University, Waltham, Mass. (Postdoctorate)

Selected Publications of Prof. Eva-Maria Mandelkow »

Research Award 2006 – Prof. Harald Steiner

Prof. Harald Steiner

Project description

g-Secretase is one of two proteases responsible for the generation of the Alzheimer´s disease causing amyloid b-peptide (Ab).Understanding the precise mechanism of Ab generation is crucial for drug targeting the disease.

The Alzheimer Research Award of the Hans and Ilse Breuer Foundation strongly supports our research activities on an in-depth functional and structural characterization of g-secretase. This ambitious project concentrates on the purification of g-secretase and the analysis of its molecular architecture, on the role of modulatory interactors of g-secretase, such as CD147 and TMP21, on the identification of additional g- secretase modifiers, on the identification and characterization of g-secretase substrate and modulator binding sites, as well as on g-secretase subunit structure-function analyses.

Curriculum vitae

Name	Prof. Harald Steiner
Place of birth	Stuttgart, Germany
Date of birth	05.02.1965
since 2007	Apl. Professor of Biochemistry at the LMU München
seit 2007	Akademischer Oberrat at the Adolf- Butenandt- Institute of the LMU München
2003-2007	Akademischer Rat at the Adolf- Butenandt- Institute of the LMU München
2002	Habilitation at the LMU München
1999-2003	Wissenschaftlicher Assistent at the Adolf- Butenandt- Institute of the LMU München
1996-1999	Postdoctoral scientist at theZI Mannheim, Department of Molecular Biology, University of Heidelberg
1996	Doctorate (Dr. rer nat.) at the LMU München
1992	Degree (Dipl.-Chem.) at the University of Stuttgart

Selected Publications of Prof. Harald Steiner »